Effect of chronic stress on tumor progression

GENARO, A.M.; DI ROSSO, M.E.

Capital Federal

Simposio; First International Symposium of DOHaD and Stress; 2017

Ibero-American Chapter of DOHaD International Society, Sociedad Argentina de Farmacología Experimental

While response to stress is a necessary survival mechanism, prolonged stress can have several repercussions affecting behavioral, endocrine and immunological parameters. Stress mediators, which include the classic neuroendocrine hormones of the stress system (catecholamines and glucocorticoids), but also several other neurotransmitters, cytokines and growth factors, regulate homeostasis and might mediate the pathogenesis of stress- related diseases. In particular, epidemiological studies indicate that chronic stress might constitute a risk factor for cancer onset and progression.The role of psychosocial factors in cancer initiation has been ambiguous; however the influence of stress on cancer progression has been demonstrated. In vitro, in vivo, and clinical studies show that stress related processes can impact pathways implicated in cancer progression, including immuno regulation, angiogenesis, and invasion. Most of the studies in animal models regarding this topic put the focus on the neuroendocrine modulation of the immune response to tumor cells. However, if stress mediators might directly modulate the growth and malignant behavior of tumor cells, independent of effects on the immune system, has been less analyzed. Moreover, in general, these studies have been developed in athymic nude or SCID mice, analyzing the influence of stress on tumor invasion and metastasis independently of the influence of immune system. In this scenario, our aim is to investigate the effect of chronic stress on tumor progression considering both its influence on immune system and its action on tumor biology. For this purpose, we worked with a solid tumor using EL-4 T cell lymphoma cells growing in C57BL/6 female mice submitted or not to a chronic variable stress model. Our results indicate that chronic stress induce cancer progression, and cause several molecular alterations in tumors. PCNA and Cyclins D1, D3 and A2 mRNA expression are enhanced in tumors from stressed mice. Furthermore, spontaneous and experimental metastasis assays showed that chronic stress enhances tumor invasion. This is accompanied by the increase of invasion markers mRNA levels. Furthermore, antitumor immune response is decreased in stressed mice. Fluoxetine (F) and sertraline (S), two selective serotonin reuptake inhibitors, are widely used for the treatment of depressive symptoms of cancer patients although there are contradictory evidences about its effects on immunity and neoplastic processes. So, we also study the effect of F or S on chronic stress-induced molecular alterations related to cell invasion and decrease of antitumor response.Our results suggest that chronic antidepressant treatment prevents enhanced tumor evolution by reversing tumor cell invasion capacity and decrease in antitumor response induced by chronic stress. Our growing understanding of novel pharmacological actions of these drugs provides new perspectives in cancer therapy.